The present invention relates to compounds which broadly may be considered as pregnadienoic acid derivatives. In addition, the compounds with which the present invention is concerned are derived from a basic prednisolone ring structure and thus may be termed prednisolone derivatives. Hereinafter the terms "pregnadienoic acid derivatives" and "prednisolone derivatives" will be used interchangeably to designate the general class of compounds with which the compounds of the present invention are believed to be associated.
Prednisolone is a potent pharmaceutical agent which has been commercially available for many years. Prednisolone is characterized by pronounced anti-inflammatory activity, when administered locally or systemically, coupled with a significant suppression of the pituitary-adrenal axis. Usually, prednisolone is administered for its anti-inflammatory effect and the associated pituitary-adrenal axis inhibition is often considered as a serious, major side effect resulting from the administration of prednisolone. Indeed, adrenal inhibition is often considered the major disadvantage of using many of the corticosteroid anti-inflammatory drugs. Even so, one should bear in mind that in certain disease states and medical conditions, such as manifestations of hyperadrenocorticalism, suppression of plasma cortisol is desired, so in that instance the drug's anti-inflammatory activity could be considered an undesirable side effect.
Most often, the corticosteroid compounds are being administered for their anti-inflammatory effect. Although a number of potent corticosteroid compounds have been commercially developed for use as local and systemic anti-inflammatory agents, essentially all of them produce an undesired adrenal inhibition side effect, even when only administered topically, such as where large surface body areas are involved and/or prolonged treatment times are needed.
One approach to the problem of pituitary adrenal axis suppression occurring from topical administration of steroid drugs has been to employ dosage forms tailored for local application while reducing systemic absorption. Recently, another approach has been investigated, which involves the chemical modification of corticosteroid compounds to develop chemical structures which divorce the anti-inflammatory activity of the corticosteroid from the pituitary-adrenal suppression activity thereof. Some successes have been reported in this area, which is the general area of structural-activity relationships to which the present invention is directed. Although the main thrust has been to structurally modify base corticosteroid structures to retain or enhance anti-inflammatory properties while reducing pituitary adrenal axis suppression, the inventor again notes that at times the medical condition being treated requires the opposite approach, that is to retain the pituitary adrenal axis suppression properties while reducing the anti-inflammatory characteristics of the steroid drug.
As will be explained more fully hereinbelow, the present invention is concerned with corticosteroid compounds, which as noted above may broadly be considered as pregnadienoic acid derivatives or as prednisolone derivatives, which compounds are characterized by a pharmacological spectrum of activity which is (A) significant anti-inflammatory activity without significant pituitary-adrenal axis suppression, (B) significant adrenal inhibition without significant anti-inflammatory activity or (C) both of significant anti-inflammatory activity and significant pituitary-adrenal axis suppression activity.
Henry J. Lee and co-workers at Florida A & M University, Tallahassee, Fla., have published a number of papers on their so-called "P4" and "P8" compounds. "P8" is stated to be methyl prednisolonate; "P4". is described as methyl 20-dihydroprednisolonate. In order to avoid any ambiguity in nomenclature, "prednisolone" is used herein to designate the structure 11.beta.,17,21-trihydroxy-1,4-pregnadiene-3,20-dione. Thus, methyl prednisolonate is the same as the compound named methyl 11.beta.,17-dihydroxy-3,20-dioxo-1,4-pregnadien-21-oate. Structurally, "P4" and "P8" are illustrated by Lee et al as follows: ##STR1##
Regarding the work of Lee et al, see Solimon, M. R. I., et al "New Anti-inflammatory Steroids: Steroid-21-oate Esters" 6th Ann. Clin. Sympo., Prog. Res. Clin. App. Corticoids, Proceedings of December 1981; Lee, Henry J. et al, "Binding of Glucocorticoid 21-oic Acids and Esters to Molybdate-Stabilized Hepatic Receptors", Journal of Steroid Biochemistry, Vol. 14, p. 1325 (1981); Heiman, Ann S., et al, "Stabilization of Rat Liver Lysozymes by New Anti-Inflammatory Steroids In Vitro," STEROIDS, Vol. 38, No. 4, p. 2799 (1981); Lee, Henry J., et al, "Anti-Inflammatory Steroids Without Pituitary-Adrenal Suppression," Science, Vol. 215, p. 989 (1982); Lee, Henry J., et al, "Anti-Inflammatory Activity of Two Novel Derivatives of Prednisolone", Research Communications in Chemical Pathology and Pharmacology, Vol. 27, No. 3, p. 611 (1980); Soliman, M. R. I., et al, "Local Anti-Inflammatory Activity of Acid Ester Derivatives of Prednisolone," Research Communications in Chemical Pathology and Pharmacology, Vol. 33, No. 2, (1981); DePetrillo, Thomas et al, "Two Anti-Inflammatory Steroids Which Neither Inhibit Skin Collagen Synthesis Nor Cause Skin Atrophy," (in preparation).
Lee et al synthesized their "P4" and "P8" materials using procedures worked out and published by the present inventor many years prior to the Lee et al work. See, Lewbart, M. L., et al, "Preparation and Properties of Steroidal 17,20- and 20,21-Acetonides Epimeric at C-20. II Derivatives of Cortisol and Cortisone", J. Org. Chem., 34, p. 3513 (1969). Other Lewbart et al references noted by the Lee et al publications, regarding synthesis procedures, are "Conversion of Steroid-17-yl Glyoxals to Epimeric Glycolic Ester," J. Org. Chem., 28, p. 1779 (1963) and "Oxidation of Steroidal Alpha-Ketols to Glyoxals with Cupric Acetate," J. Org. Chem., 28, p. 2001, (1963). In addition, the present inventor has co-authored a number of other articles published in the Journal of Organic Chemistry related to steroidal synthesis steps; however, the present invention is not concerned with steroidal compound preparation.
In reviewing the Lee et al published articles it is found that the "P4" material as synthesized and tested in accordance with the Lee et al publications would in actuality be a mixture of compounds and would be expected to contain both the 20-.alpha. and 20-.beta. epimers of methyl 20-dihydroprednisolonate. This may explain the different results obtained at times by Lee et al. Subsequent contacts between the present inventor and Lee have confirmed that Lee et al's published "P4" comprises an epimeric mixture, usually with the 20-.alpha. and 20-.beta. epimers being present in a ratio of about 10:1, with the "P4" material also containing small amounts of unknown impurities.
Laurent et al, U.S. Pat. No. 3,994,577, disclose pregnan-21-oic acids and esters thereof stated to have topical anti-inflammatory activity with substantially no systemic activity. The Laurent et al compounds are characterized by carbonyl at C-20. In addition, Laurent et al disclose synthesis of their target compounds through intermediates of their formula III, as follows: ##STR2## which includes the methyl ester of 11.beta.,17.alpha.,20.epsilon.-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid (Example 15 of U.S. Pat. No. 3,944,577). Thus, Laurent et al, also using the copper acetate method of Lewhart et al, do correctly note the epimeric mixture (20.epsilon.). Related work of Laurent et al is found in "New Biologically Active Pregnan-21-oic Acid Esters", J. of Steroid Biochemistry, 6, p. 185 (1975), where many C-20 epimers, but not including those of the present invention, are described. Laurent et al are concerned with synthesis of corticoid derivatives for use as possible local anti-inflammatory agents without systemic side effects. Their preferred compounds include a fluorine ring substituent. Another disclosure of the methyl ester of 20-dihydro-prednisolonate is found in German 1173467 by Daase et al.